Modulation of transforming growth factor-β-binduced kidney fibrosis by leucine-rich α-2 glycoprotein-1

Kidney fibrosis is considered the final convergent pathway for progressive chronic kidney diseases, but there is still a paucity of success in clinical application for effective therapy. We recently demonstrated that the expression of secreted leucine-rich alpha-2 glycoprotein-1 (LRG1) is associated with worsened kidney outcomes in patients with type 2 diabetes and that LRG1 enhances endothelial transforming growth factor-beta signaling to promote diabetic kidney disease progression. While the increased expression of LRG1 was most prominent in the glomerular endothelial cells in diabetic kidneys, its increase was also observed in the tubulointerstitial compartment. Here, we explored the potential role of LRG1 in kidney epithelial cells and TGF-beta- mediated tubulointerstitial fibrosis independent of diabetes. LRG1 expression was induced by tumor necrosis factor-a in cultured kidney epithelial cells and potentiated TGF-beta/Smad3 signal transduction. Global Lrg1 loss in mice led to marked attenuation of tubulointerstitial fibrosis in models of unilateral ureteral obstruction and aristolochic acid fibrosis associated with concomitant decreases in Smad3 phosphorylation in tubule epithelial cells. In mice with kidney epithelial cell-specific LRG1 overexpression, while no significant phenotypes were observed at baseline, marked exacerbation of tubulointerstitial fibrosis was observed in the obstructed kidneys. This was associated with enhanced Smad3 phosphorylation in both kidney epithelial cells and asmooth muscle actin-positive interstitial cells. Co-culture of kidney epithelial cells with primary kidney fibroblasts confirmed the potentiation of TGF-beta-mediated Smad3 activation in kidney fibroblasts through epithelial-derived LRG1. Thus, our results indicate that enhanced LRG1 expression-induced epithelial injury is an amplifier of TGF-beta signaling in autocrine and paracrine manners promoting tubulointerstitial fibrosis. Hence, therapeutic targeting of LRG1 may be an effective means to curtail kidney fibrosis progression in chronic kidney disease.

Automated summary

The abnormal expression of secreted leucine-rich alpha-2 glycoprotein-1 (LRG1) is associated with the progression of chronic kidney diseases, promoting kidney fibrosis through enhanced endothelial transforming growth factor-beta (TGF-beta) signaling. LRG1 expression increases in glomerular endothelial cells and the tubulointerstitial compartment. In mouse models, loss of LRG1 attenuated kidney fibrosis, while overexpression exacerbated fibrosis. These findings suggest that therapeutic targeting of LRG1 may effectively halt the progression of kidney fibrosis in chronic kidney disease.